HIV-infected women have at least fourteen times the risk of developing anal carcinoma compared with the general population despite the widespread use of highly active antiretroviral therapy (HAART). Like cervical cancer, anal cancer appears to be preceded by high-grade intraepithelial neoplasia and is strongly associated with human papillomavirus (HPV) infection. The prevalence of anal precancerous lesions among HIV-infected women has been shown to be as high as 10%. Due to this alarming increase in anal precancerous and cancerous lesions among HIV-infected women, there has been an increasing emphasis on anal cancer prevention, including recommendations in the 2007 New York state HIV primary care guidelines to perform annual anal cytology testing among HIV-infected women with a history of abnormal cervical or vulvar histology or history of anogenital condyloma. However, little to no evidence exists to define the optimal screening strategy for anal intraepithelial neoplasia (AIN) in the context of HIV-infected women. In the HAART era, there have been no studies of HIV-infected women in which high resolution anoscopy (HRA) with directed biopsy was performed on all participants with concurrent sampling for anal cytology and HPV testing. Therefore the prevalence of high-grade anal intraepithelial neoplasia (HGAIN) is not known, nor are the risk factors for developing this lesion. HPV testing has been shown to be a useful adjunct to cervical cytology for cervical cancer screening , however, we do not know if using HPV to triage HIV-infected women with abnormal anal cytology would be of benefit. Therefore, our specific aims are: Specific aim 1a: to determine the sensitivity (through confirmation of cytological abnormalities using HRA-guided anal biopsies) and specificity (through HRA confirmation of normal cytology) of anal cytology testing at the initial study visit among HIV-infected women. Specific aim 1b: to determine if anal high risk (HR) HPV testing using different methods of HPV detection, including HPV Hybrid Capture 2 (HC2) and HPV mRNA assays (APTIMA), will improve the screening test characteristics of routine anal cytology testing alone. Specific Aim 2: to determine the baseline prevalence rate, and risk factors associated with HGAIN and anal HPV;and to quantify HGAIN and anal HPV incidence, and prevalence rate changes over time among HIV-infected women undergoing routine anal cytologic testing, and specific Aim 3: to perform an economic evaluation of different anal cytology testing strategies among HIV-infected women. In order to address these aims, we propose a two-site, multidisciplinary study, utilizing data collected from a 2-year longitudinal cohort study of 300 HIV-infected women who will be evaluated at 6 month intervals. This cohort study will be the first to provide important information regarding the test characteristics, epidemiology, and natural history of anal HPV infection and HGAIN among a cohort of HIV-infected women undergoing routine anal cytology testing. The data will then be utilized to perform comprehensive cost-benefit analyses, which will direct clinical decision making on an optimal anal cancer screening approach for these women. PUBLIC HEALTH RELEVANCE: HIV-infected women have at least fourteen times the risk of developing anal carcinoma compared with the general population despite the widespread use of highly active antiretroviral therapy (HAART). Like cervical cancer, anal cancer appears to be preceded by high-grade anal intraepithelial neoplasia and is strongly associated with human papillomavirus (HPV) infection. This longitudinal study will provide the necessary information to make policy guidelines for screening for anal cancer in HIV-infected women as well as better characterizing the progression of HPV infection and high-grade anal intraepithelial neoplasia in HIV-infected women in the HAART era.